1. Technical Field of the Invention
The present invention relates to the administration of an effective amount of 4,6-dimethoxyindole-2-carboxylic acid or derivative or composition comprised thereof, to induce and/or stimulate hair growth and/or to prevent hair loss.
2. Description of the Prior Art
In human subjects, the growth and renewal of the hair are principally determined by the activity of the hair follicles. This activity is cyclic and essentially comprises three phases, i.e., the anagenic phase, the catagenic phase and the telogenic phase.
The active anagenic phase, or growth phase, which lasts for several years and during which the hair becomes longer, is followed by a very short and transient catagenic phase which lasts a few weeks, and then a rest or quiescent phase, known as the telogenic phase, which lasts a few months.
At the end of the rest period, the hair falls out and another cycle begins. The head of hair is thus under constant renewal, and out of the approximately 150,000 hairs on a human head of hair, at any given moment, approximately 10% of them are at rest and will thus be replaced within a few months.
However, different causes can lead to a considerable, temporary or permanent, loss of hair. Alopecia is essentially due to a disruption in hair renewal which gives rise, in a first stage, to an acceleration of the frequency of the cycles, at the expense of the quality of the hair and then at the expense of its quantity. A gradual depletion of the head of hair takes place by regression of the so-called xe2x80x9cterminalxe2x80x9d hairs at the downy stage. Regions are preferentially affected, in particular the temples or frontal bulbs in men, and in women diffuse alopecia of the vertex is observed.
The term xe2x80x9calopeciaxe2x80x9d is generic to the entire family of afflictions of the hair follicle, the final consequence of which is the partial or general permanent loss of the hair. In a large number of cases, early loss of the hair occurs in genetically predisposed individuals and especially is prevalent in men. This ie more particularly the case as regards androgenetic or androgenic or even androgeno-genetic alopecia.
Active agents for suppressing or reducing alopecia, and in particular for inducing or stimulating hair growth or reducing hair loss, have long been considered desiderata in the cosmetics and pharmaceutical industries.
In this respect, a large number of very diverse active compounds have already been proposed for such purposes, for example, 2,4-diamino-6-piperidino-pyrimidine 3-oxide or xe2x80x9cMinoxidilxe2x80x9d as described in U.S. Pat. Nos. 4,139,619 and 4,596,812, or the many derivatives thereof, such as those described, for example, in EP-0,353,123, EP-0,356,271, EP-0,408,442, EP-0,522,964, EP-0,420,707, EP-0,459,890 and EP-0,519,819.
Specific compounds of the indolecarboxylic family, such as those described in WO-A-99/12905, have also been proposed for their ability to induce and/or stimulate hair growth and/or to prevent hair loss.
These compounds exhibit pronounced inhibitory activity on type I and type II 5xcex1-reductases, which, according to the theory which considers that these proteins are involved in hair loss, makes them excellent candidates as active principles for inducing and/or stimulating hair growth and/or for preventing hair loss.
However, 5xcex1-reductases are not exclusively present in the hair follicles, and the value of providing compounds suited for inducing and/or stimulating hair growth and/or of preventing hair loss, but which have no activity on type I and II 5xcex1-reductases, consequently, can readily be appreciated.
It has now surprisingly and unexpectedly been determined that 4,6-dimethoxyindole-2-carboxylic acid and derivatives thereof have the property of inducing and/or stimulating hair growth and/or of preventing hair loss, but do not exhibit any activity on type I and type II 5xcex1-reductases.
Briefly, the present invention features cosmetic/dermatological compositions comprising a therapeutically effective amount of at least one compound having the structural formula (I): 
in which R1 and R2, which may be identical or different, are each a hydrogen atom; a C1-C6 alkyl radical, optionally substituted with an xe2x80x94OH, xe2x80x94NHR3, xe2x80x94SH, xe2x80x94COOH or xe2x80x94COOR3 radical, in which R3 is a linear or branched C1-C4 alkyl radical; a C7-C12 aralkyl radical; or a radical xe2x80x94CHR4R5, wherein R4 and R5, which may be identical or different, are each a hydrogen atom, an optionally substituted phenyl radical, or a 5- or 6-membered heterocycle; the acylated derivatives or the physiologically acceptable salts thereof, either singly or in any admixture in any proportion; said compound and/or said compositions being well suited to induce and/or stimulate hair growth and/or to prevent hair loss.
More particularly according to the present invention, the subject compounds exhibit marked utility as active principles for inducing and/or stimulating hair growth and/or for preventing hair loss.
It was hitherto unknown to administer such compounds for combating hair loss.
According to the invention, by the term xe2x80x9cheterocyclexe2x80x9d is preferably intended a ring optionally including one or more nitrogen and/or oxygen atoms, and particularly pyridine, imidazole, tetrahydrofuran or furan. One heterocycle which is particularly preferred according to the invention is pyridine.
By the expression xe2x80x9cC1-C4 alkyl radicalxe2x80x9d are intended linear or branched acyclic radicals having from 1 to 4 carbon atoms, derived from the removal of a hydrogen atom from a hydrocarbon molecule, and in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl radicals.
By the expression xe2x80x9cC7-C12 aralkyl radicalxe2x80x9d are preferably intended alkylaryl radicals containing from 7 to 12 carbon atoms, in which definition the term xe2x80x9carylxe2x80x9d connotes an aromatic ring containing 5 or 6 carbon atoms or an aromatic heterocycle containing 5 or 6 atoms. According to the invention, the aralkyl radical is preferentially C7-C10. One aralkyl radical which is particularly preferred according to the invention is the benzyl radical.
And by the expression xe2x80x9coptionally substituted phenyl radicalxe2x80x9d is preferably intended a phenyl radical optionally substituted with a cyano (xe2x80x94CN) group, a trifluoromethyl (xe2x80x94CF3) group, a methoxy (xe2x80x94Oxe2x80x94CH3) radical or a halogen atom. The halogen atom can be selected from among chlorine, bromine, fluorine and iodine. One substituted phenyl radical which is particularly preferred according to the invention is a phenyl radical substituted with a trifluoromethyl (xe2x80x94CF3) group.
In one preferred embodiment of the invention, R1 is a hydrogen atom or a methyl or ethyl radical.
In another preferred embodiment of the invention, R2 is a hydrogen atom or a methyl radical.
And in a very preferred embodiment of the invention, R1 and R2 are each a hydrogen atom.
Exemplary compounds of formula (I) include:
4,6-dimethoxyindole-2-carboxylic acid;
methyl 4,6-dimethoxyindole-2-carboxylate;
N-methyl-4,6-dimethoxyindole-2-carboxylic acid;
methyl N-methyl-4,6-dimethoxyindole-2-carboxylate;
N-ethyl-4,6-dimethoxyindole-2-carboxylic acid.
Among these compounds, that most particularly preferred is 4,6-dimethoxyindole-2-carboxylic acid.
According to the invention, the subject compounds can be used alone or as a mixture.
It will of course be appreciated that the effective amount of compound to be administered corresponds to the amount required to elicit the desired result. One skilled in this art is thus capable of evaluating this effective amount, which depends on the nature of the compound and on the person thus treated. To provide an order of magnitude, in the compositions according to the invention the compound of formula (I) is typically present at a concentration ranging from 0.3% to 30% by weight relative to the total weight of the composition and preferably from 0.5% to 20%.
According to the invention, the compounds of formula (I) can be formulated into any suitable medium (vehicle, diluent or carrier) for cosmetic or pharmaceutical applications. The compounds of formula (I) are preferentially formulated into compositions for cosmetic application.
The physiologically acceptable medium in which the active agent is formulated according to the invention is anhydrous or aqueous. By the expression xe2x80x9canhydrous mediumxe2x80x9d is intended a solvent medium containing less than 1% water. This medium is a solvent or a mixture of solvents selected more particularly from among C2-C4 lower alcohols such as ethyl alcohol, alkylene glycols such as propylene glycol, and alkylene glycol alkyl ethers or dialkylene glycol alkyl ethers, the alkyl or alkylene radicals of which have from 1 to 6 carbon atoms. By the expression xe2x80x9caqueous mediumxe2x80x9d is intended a medium of water or of a mixture of water and another physiologically acceptable solvent, selected in particular from among the organic solvents indicated above. In this latter instance, when these other solvents are present, they constitute approximately 5% to 95% by weight of the composition.
The physiologically acceptable medium can also contain other adjuvants and additives usually formulated into cosmetics or pharmaceuticals, such as surfactants, thickeners or gelling agents, cosmetic agents, preservatives, and acidifying and basifying agents that are well known to the prior art, and in amounts that are sufficient to provide the desired presentation form, in particular a more or less thickened lotion, a gel, an ointment, a milk, an emulsion or a cream. The composition can optionally be provided in a form pressurized as an aerosol or vaporized from a pump-dispenser bottle.
The subject active agents can also be formulated in combination with compounds for further improving the activity on hair growth and/or on preventing hair loss, which have already been described for such activity.
Among these, more particularly exemplary are:
(a) nicotinic acid esters, in particular tocopheryl nicotinate, benzyl nicotinate and C1-C6 alkyl nicotinates such as methyl or hexyl nicotinate;
(b) pyrimidine derivatives, such as 2,4-diamino-6-piperidinopyrimidine 3-oxide or xe2x80x9cMinoxidilxe2x80x9d described in U.S. Pat. Nos. 4,139,619 and 4,596,812;
(c) agents for promoting hair regrowth, such as those described in the European patent application published under No. 0,648,488 assigned to the assignee hereof;
(d) antibacterial agents such as macrolides, pyranosides and tetracyclines, and in particular erythromycin;
(e) calcium antagonists such as Cinnarizine, Diltiazem, Nimodipine and Nifedipine;
(f) hormones, such as estriol or analoges thereof, or thyroxine and salts thereof;
(g) steroidal anti-inflammatory agents, such as corticosteroids (for example hydrocortisone);
(h) antiandrogenic agents, such as oxendolone, spironolactone, diethylstilbestrol and flutamide;
(i) steroidal or non-steroidal 5xcex1-reductase inhibitors such as finasteride;
(j) potassium agonists such as cromakalim and nicorandil.
Other compounds are also representative additives, for example, diazoxide, spiroxazone, phospholipids such as lecithin, linoleic acid, linolenic acid, salicylic acid and derivatives thereof described in FR-2,581,542, for instance salicylic acid derivatives bearing an alkyl radical having from 2 to 12 carbon atoms in position 5 of the benzene ring, hydroxycarboxylic or ketocarboxylic acids and esters thereof, lactones and the corresponding salts thereof, anthralin, carotenoids, eicosatetraenoic and eicosatrienoic acids or esters and amides thereof, vitamin D and derivatives thereof, and extracts of plant or bacterial origin.
The compositions comprising at least one compound of formula (I) can also be formulated in liposomal form, as described, in particular, in WO-94/22468, filed Oct. 13, 1994 by the company Anti-Cancer Inc. Thus, the compound encapsulated in the liposomes can be delivered selectively to the hair follicles.
The cosmetic compositions according to the invention can be topically applied onto the alopecic regions of the scalp and hair of an individual, and are optionally maintained in contact for several hours and then optionally rinsed therefrom. For example, the compositions containing an effective amount of at least one compound as described above can be applied in the evening, maintained in contact throughout the night and optionally shampooed out in the morning. These applications can be repeated daily for one or more months depending on the particular individual.
Thus, the present invention also features a cosmetic regime/regimen for treating the hair and/or the scalp, comprising topically applying onto the hair and/or the scalp a cosmetic composition which comprises an effective amount of at least one compound of formula (I), in maintaining this composition in contact with the hair and/or the scalp, and optionally rinsing same therefrom.
Such regime/regimen has the characteristics of a cosmetic methodology since it improves the aesthetics of the hair by rendering it more vigorous and better in appearance.